The present invention discloses a new and economical process for preparation of ceftiofur acid starting from ceftiofur acid hydrohalide salt and treating it with a trimethylsilylating agent. The ceftiofur acid thus prepared was converted into its sodium slat by using some highly efficient sodium exchange reagent.
Ceftiofur acid is the generic name given to a compound of formula (I) 
ceftiofur acid, its salts with alkali metal, alkaline earth metal and amines are reported for the first time in U.S. Pat. No. 4,464,367. All these derivatives of ceftiofur acid are known to have stability problems and are difficult to purify due to the amorphous nature of the compounds.
An attempt to overcome these problems was made in U.S. Pat. No. 4,877,782 by preparing zinc complexes of ceftiofur acid which have better dispersibility in water and can be used in pharmacological preparations. U.S. Pat. No. 4,902,683, explains the isolation of ceftiofur acid in the form of crystalline hydrohalide salts which has better solubility and other physical properties compared to parent compounds. The hydrohalide salts as such cannot be used for parenteral administration, therefore it is necessary to convert to a hydrohalide salt to sodium salt in order to use the drug as injectable.
Several methods are reported in patents for converting cephalosporanic acid to their corresponding alkali metal salt. This step is of special importance in the case of injectable antibiotics. Surprisingly, very few methods are disclosed for preparing ceftiofur sodium starting from hydrohalide salt of ceftiofur acid. U.S. Pat. No. 4,937,330 describes the use of polyvinylpyridine for neutralization of hydrohalide salt to get free acid and then treating the free acid with sodium-2-ethylhexanoate. The use of sodium-2-ethyl hexanoate for this purpose is the subject of several patents in the field of ceftiofur sodium antibiotics. The neutralization of hydrohalide salt using polyvinyl pyridine resin involves an extra filtration step in the process and the resin loses activity after certain batches and needs replacement which adds cost to the process.
In general, the process for liberation of ceftiofur acid free acid from hydrohalide salt using either resinous bases or non-resinous bases is associated with several problems. Keeping all these problems in mind, the Applicant discloses a simple, economical and commercially viable process for preparing ceftiofur sodium starting from ceftiofur acid hydrohalide salt which obviates the above mentioned limitations and does not use known neutralizing agents for this purpose. The process comprises two steps:
(a) treatment of hydrohalide salt of ceftiofur acid with trimethylsilylating agent which will neutralize the ceftiofur acid hydrohalide salt to give free ceftiofur acid; and
(b) the reaction of free ceftiofur acid with sodium exchanging agents for making sodium salt of ceftiofur acid.
The primary object of the invention is a new process for preparing a ceftiofur sodium.
Another object of this invention is to neutralize the hydrohalide salt of ceftiofur acid to get free ceftiofur acid. This has been achieved by using N,O-bistrimethylsilyl acetamide, bis-trimethylsilylurea and Hexamethyl disilazane (HMDS). The applicant reports for the first time the use of these trimethylating agents for the purpose of neutralizing the hydrohalide salt of any cephem acid.
Yet another object of the invention relates to use of trimethylsilylating agent for the first time for the purpose of neutralizing the hydrohalide salt of any cephem acid.
Still another object of this invention is to make sodium salt thus prepared from ceftiofur acid using sodium lactate, sodium ethylacetoacetate, sodium-2-ethyl hexanoate and sodium acetate as sodium exchange reagent.
The present invention relates to a process for preparing sodium salt of cephalosporins from their corresponding hydrohalide salt, which is neutralized with trimethylsilylating agent for the first time.